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dc.contributor.advisorJavier Irazoquien_US
dc.contributor.authorGoswamy, Debanjan
dc.description.abstractDetection of pathogenic signals leads to extensive changes in cellular transcriptional programs mediated by transcription factors. Positive and negative regulators of this host defense response work together to maintain immune homeostasis. Over the past two decades, several evolutionary conserved positive regulators of innate immunity have been identified in C. elegans. However, negative regulators remain unknown, and repression of the host defense response poorly understood. We previously discovered that HLH-30/TFEB is a positive regulator of immunity in C. elegans and murine macrophages after S. aureus infection, respectively. In this study, I identify nhr-42 as a negative regulator of immunity functioning downstream of HLH-30, with major implications for host survival, metabolism, and fitness. In nhr-42 mutants, several host defense genes, such as antimicrobial peptides, C-type lectins, and lysozymes, are upregulated constitutively. This enables nhr-42 mutants to have enhanced survival and lower pathogen burden after infection compared to wild type animals. I show that nhr-42 expression is induced in the pharynx and pharyngeal-intestinal valve after infection. Furthermore, I find that antimicrobial peptides abf-2 and cnc-2 are required for enhanced survival and lower pathogen burden in nhr-42 mutants. Moreover, induction of nhr-42 after infection leads to upregulation of lipid catabolism genes involved in beta-oxidation, driving lipid mobilization. These data show that nhr-42 functions to limit the host defense response to maintain immune homeostasis and reallocate energy resources through lipid mobilization towards other cellular processes. Additionally, I identify Nr1d1 (Rev-Erbα) as a functional homolog of nhr-42. I show that Nr1d1 functions downstream of TFEB to negatively regulate pro-inflammatory cytokines Il-6 and Il1b in macrophages, after S. aureus infection. These data open up new research avenues into mammalian nuclear receptor mediated regulation of immunity.en_US
dc.publisherUMass Chan Medical Schoolen_US
dc.rightsCopyright © 2022 Goswamyen_US
dc.subjectinnate immunityen_US
dc.subjectnuclear hormone receptorsen_US
dc.subjectnegative regulation of immunityen_US
dc.subjectC. elegansen_US
dc.subjectS. aureusen_US
dc.titleNegative regulation of innate immunity by novel nuclear receptor NHR-42/NR1D1 with implications in infection survival, metabolism, and fitnessen_US
dc.typeDoctoral Dissertationen_US
dc.contributor.departmentMicrobiology and Physiological Systemsen_US
dc.description.thesisprogramImmunology and Microbiologyen_US

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